DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/11/2025 has been entered.
Receipt is acknowledged of an amendment, filed on 12/11/2025, in which claims 30, 40 and 89 were amended, claims 31, 35, 41, 58, 87, 88 and 90-94 were previously presented and claim 62 was canceled.
Claims 30, 31, 35, 40, 41, 58 and 87-94 are currently under examination.
Election/Restrictions
Applicant's election without traverse of Group III, drawn to a method of producing a DNA vector in the reply filed on 12/31/2024 is acknowledged.
Applicant's election without traverse of the elected species, AAV2 Rep 78, a mutation at
amino acid position 225 of SEQ ID NO: 588 as well as SEQ ID Nos: 2 and 52 as the first and
second ITRs, respectively in the reply filed on 12/31/2024 is acknowledged.
Claim 86 is withdrawn from further consideration pursuant to 37 CPR 1.142(b) as being
drawn to a nonelected species, there being no allowable generic or linking claim. Election was
made without traverse in the reply filed on 12/31/2024.
Claims 30, 31, 35, 40, 41, 58 and 87-94 are under consideration.
Response to Arguments - Claim Rejections - 35 USC§ 102
The rejection of claims 30, 31, 35, 40, 41, 58, 87, 88, 92, 93 and 94 under 35 U.S.C.
102(a)(l) as being anticipated by Wang et al (Journal of Virology, Vol 80 No 23, pages 11699-
11709; 2006), as evidenced by Lubarsky et al (CA 2,596,303) has been withdrawn in view of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 30, 31, 35, 40, 41, 58, 87, 88, 92, 93 and 94 are rejected under 35 U.S.C.
103 as being unpatentable by Kotin et al (WO 2017/152149 A1) in view of Holscher et al
(Journal of Virology, Vol 69 No 11, Pages 6880-6885; 1995). This is a NEW rejection necessitated by amendment.
Regarding claims 30, 40, 41, 58 and 62, Kotin teaches the method of producing nucleic acid constructs within a cell by introducing into a cell a nucleic acid comprising a heterologous nucleic acid insert (e.g. transgene) flanked by interrupted self-complementary sequences wherein the permissive cell expresses a rolling circle replication protein but does not express viral particle as well as maintaining the cell under conditions in which the rolling circle replication protein replicates the nucleic acid (Page 8; Lines 6-16). Kotin teaches the transgene includes control elements that permit transcription and translation of the nucleic acid (Page 44; Lines 29-32). Kotin teaches the method also comprises isolating the replicated nucleic acid from the cell (Page 8; Lines 17-18). Kotin teaches the structure of a linear and continuous DNA vector with ITRs on both ends creating a duplex closed-end DNA construct (Figure 2A and 2B; Page 9, lines 28-31 to Page 10 lines 1-2). Kotin teaches the DNA vector as a ceDNA with asymmetric AAV ITRs as well as protein expression of a Rep78 protein (Page 65, lines 26-32 to page 66, lines 1-9). Kotin teaches the rolling circle replication proteins include at least one selected from AAV Rep78, AAV Rep 68, AAV Rep 52 and AAV Rep 40 (Page 7; Lines12-14). Kotin teaches that the Rep78 protein is capable of DNA nicking at the site-specific terminal resolution site (Page 65; Lines 30-32). Kotin teaches that each interrupted self-complementary nucleic acid sequence includes an operative rep-binding element and an operative terminal resolution site (trs) (Page 67; Lines 18-20). Kotin teaches purification and retrieval of the ceDNA products from cells (Page 66, Lines 20-32).
Kotin does not teach strict expression of only Rep78 protein or only Rep68 protein.
Holscher teaches that expression of Rep78 alone is sufficient for production of infectious rep-negative AAV in HeLa cells (Page 6881; Column 1 bridging column 2). Holscher teaches that the introduction of pCMRep78 and pTAV2-3 into HeLa cells led to the production of infectious rep-negative AAV, with pCMRep78 being more efficient than pCMRep68 (Page 6881; Column 2). The pCMRep78 construct comprises a mutant Rep78 nucleic acid as compared to the endogenous AAV nucleic acid sequence which encodes multiple Rep proteins from the same nucleic acid sequence (Page 6880 Paragraph bridging the columns). Furthermore, Holscher teaches that enhanced Rep78 expression leads to the production of infectious rep-negative AAV in three additional cell lines (Page 6881; Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Kotin to specifically express only Rep78 in the cell by contacting the cell with a nucleic acid encoding Rep78 as the only species of Rep protein, as taught by Holscher, because Kotin teaches that it is within the skill of the art to express Rep78 and Rep52 for the purpose of producing a closed-ended DNA vector based on AAV replication and suggest that only Rep78 is expressed, and Holscher teaches it is within the ordinary skill in the art to contact a cell with a nucleic acid encoding only AAV Rep 78 without for a functional coding sequence for Rep52 to provide for AAV replication in a cell., One would have substituted the polynucleotide encoding Rep78 and Rep52 of Kotin with the polynucleotide encoding only Rep78 of Holscher in order to achieve the predictable result of providing a necessary and sufficient protein for AAV replication in the cell to result in the production of the closed-ended AAV vector.
Regarding claims 31, 35, 87 and 88, Kotin teaches the Rep78 protein from AAV2 is used within the method (Page 65 line 32 to Page 66 line 2).
Regarding claims 92, Kotin teaches the heterologous nucleic acid (e.g., transgene) comprises 10-5,000 base pairs (Page 22; Lines 11-25).
Regarding claims 93 and 94, Kotin teaches the heterologous nucleic acid (e.g., transgene) encodes a protein such as a reporter protein or therapeutic protein (Page 22; lines 1-10).
Kotin does not teach strict expression of only Rep78 protein by contacting the cell with a nucleic acid encoding Rep 78. Kotin does not teach the Rep78 protein is encoded by a mutant Rep78 nucleic acid.
Holscher teaches that expression of Rep78 alone is sufficient for production of infectious rep-negative AAV in HeLa cells (Page 6881; Column 1 bridging column 2). Holscher teaches that the introduction of pCMRep78 and pTAV2-3 into HeLa cells led to the production of infectious rep-negative AAV, with pCMRep78 being more efficient than pCMRep68 (Page 6881; Column 2). The pCMRep78 construct comprises a mutant Rep78 nucleic acid as compared to the endogenous AAV nucleic acid sequence which encodes multiple Rep proteins from the same nucleic acid sequence (Page 6880 Paragraph bridging the columns). Furthermore, Holscher teaches that enhanced Rep78 expression leads to the production of infectious rep-negative AAV in three additional cell lines (Page 6881; Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Kotin to specifically express only Rep78 in the cell by contacting the cell with a nucleic acid encoding Rep78 as the only species of Rep protein, as taught by Holscher, because Kotin teaches that it is within the skill of the art to express Rep78 and Rep52 for the purpose of producing a closed-ended DNA vector based on AAV replication and suggest that only Rep78 is expressed, and Holscher teaches it is within the ordinary skill in the art to contact a cell with a nucleic acid encoding only AAV Rep 78 without for a functional coding sequence for Rep52 to provide for AAV replication in a cell. One would have substituted the polynucleotide encoding Rep78 and Rep52 of Kotin with the polynucleotide encoding only Rep78 of Holscher in order to achieve the predictable result of providing a necessary and sufficient protein for AAV replication in the cell to result in the production of the closed-ended AAV vector.
Claim 90 is rejected under 35 U.S.C. 103 as being unpatentable over Kotin et al (WO 2017/152149 A1) in view of Holscher et al (Journal of Virology, Vol 69 No 11, Pages 6880-6885; 1995) as applied to claims 30, 31, 35, 40, 41, 58, 87, 88, 92, 93 and 94 above, and further in view of Noordman et al (US 2013/0023034 Al; Cited in a prior office action). This is a NEW Rejection necessitated by amendment.
The teachings of Kotin and Holscher are described above and applied as before.
Regarding claim 90, Kotin and Holscher do not teach the mutant Rep78 protein having at least 95% identity to SEQ ID No: 588.
Noordman teaches a nucleic acid construct comprising a nucleic acid sequence encoding a mutant Rep protein [0001]. Noordman teaches the AAV Rep proteins are mutated to be different from the wildtype sequence of the AAV Rep protein [0006, 0067 & 0082]. Noordman teaches the SEQ ID NO: 2 is an AAV2 Rep78 protein. SEQ ID NO: 588 in the instant application has 100% identity to the SEQ ID NO: 2 listed in Noordman (Page 24). Noordman teaches a mutation of the wildtype Rep78 protein as SEQ IDs: 4, 8 and 10 which all share 99.7% identity to SEQ ID NO: 588 in the instant application (Page 28, 35 and 38-39). Noordman teaches the use of the Rep mutant constructs resulted in a 2-fold higher vector yield [0244].
It would have been obvious to one of ordinary skill in the art before the effective filing
date of the claimed invention to substitute the Rep78 protein sequence of Kotin and/or the Rep78 protein sequence of Holscher for the Rep78 protein sequence taught by Noordman because Kotin teaches that it is within the skill of the art to express Rep78 for the purpose of producing a closed-ended DNA vector based on AAV replication and suggest that only Rep78 is expressed, and Holscher teaches it is within the ordinary skill in the art to contact a cell with a nucleic acid encoding only AAV Rep 78 without for a functional coding sequence for Rep52 to provide for AAV replication in a cell and Noordman teaches the mutated AAV Rep 78 protein sequence.
One would have been motivated to make such a modification in order to receive the
expected benefit of increased expression of the mutated AAV Rep 78 protein as taught by Noordman.
Response to Arguments - Claim Rejections - 35 USC§ 103
The rejection of claim 90 under 35 U.S.C. 103 as being anticipated by Wang et al (Journal of Virology, Vol 80 No 23; 2006), as evidenced by Lubarsky et al (CA 2,596,303), in view of Noordman et al (US 2013/0023034 Al) has been withdrawn.
Conclusion
No claims are allowed.
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/ALEXANDRA ROSE LIPPOLIS/ Examiner, Art Unit 1637
/Jennifer Dunston/ Supervisory Patent Examiner, Art Unit 1637